Amide compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use

Abstract

Amide compounds that modulate and/or inhibit the activity of certain protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating tyrosine kinase signal transduction in order to modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer as well as other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.

What is claimed:  
     
         1 . A compound represented by the Formula I:  
       
         
           
           
               
               
           
         
         wherein: 
 R 1  is a moiety represented by the formula  
                     
  where 
 Z is selected from the group consisting of CH and NH, and Q is a moiety such that R 1  is a substituted or unsubstituted monocyclic or bicyclic heteroaryl which has at least two carbon atoms in the heteroaryl ring system;  
 X is selected from the group consisting of CH 2 , O, S, and NH;  
 Y is selected from the group consisting of CH 2 , O, and S, provided that at least one of X and Y is CH 2 , or X and Y together with the bond there-between form a cyclopropyl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, methyl, halogen, trifluoromethyl, and cyano; and  
 R 4  is selected from the group consisting of  
                     
  where R 5  is selected from the group consisting of substituted and unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, O—R 7 , NR 8 R 9 , C 1 -C 8  alkyl, and monocyclic heterocycloalkyl, R 6  is selected from the group consisting of substituted and unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, O—R 7 , C(O)R 7 , NR 8 R 9 , C 2 -C 8  alkyl, and monocyclic heterocycloalkyl, where R 7  is selected from the group consisting of substituted and unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R 8  is selected from the group consisting of hydrogen, and substituted and unsubstituted alkyl, and R 9  is selected from the group consisting of substituted and unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
 or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.  
 
 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1  is a substituted or unsubstituted heteroaryl group selected from the group consisting of:  
       
         
           
           
               
               
           
         
         X is selected from the group consisting of CH 2 , O, and S;  
         Y is selected from the group consisting of CH 2  and S, provided that at least one of X and Y is CH 2 ;  
         R 2  and R 3  are independently selected from the group consisting of hydrogen, methyl, fluorine, and chlorine, and  
         R 4  is selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
          where R 5  is selected from the group consisting of substituted and unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, O—R 7 , NR 8 R 9 , C 1 -C 8  alkyl and monocyclic heterocycloalkyl, R 6  is selected from the group consisting of substituted and unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, O—R 7 , C(O)R 7 , NR 8 R 9 , C 2 -C 8  alkyl, and monocyclic heterocycloalkyl, where R 7  is selected from the group consisting of substituted and unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R 8  is selected from the group consisting of hydrogen and substituted and unsubstituted alkyl, and R 9  is selected from the group consisting of substituted and unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
         or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.  
       
     
     
         3 . A compound represented by the Formula II:  
       
         
           
           
               
               
           
         
         wherein: 
 X is selected from the group consisting of CH 2 , O, and S;  
 Y is is selected from the group consisting of CH 2  and S, provided that at least one of X and Y is CH 2 ;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, methyl, fluorine, and chlorine;  
 R 4  is selected from the group consisting of  
                     
  where R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted aryl and heteroaryl; and R 10  is selected from the group consisting of substituted and unsubstituted alkenyl, aryl, heteroaryl, and HNR 9 , where R 9  is selected from the group consisting of substituted and unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
 or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.  
 
       
     
     
         4 . A compound according to  claim 3 , wherein R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted aryl; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite.  
     
     
         5 . A compound according to  claim 3 , wherein R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted heteroaryl; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite.  
     
     
         6 . A compound represented by the Formula III:  
       
         
           
           
               
               
           
         
         wherein: 
 X is selected from the group consisting of CH 2 , O, S, and NH;  
 Y is selected from the group consisting of CH 2 , O, and S, provided that at least one of X and Y is CH 2 , or X and Y together with the bond there-between form a cyclopropyl;  
 R 2  and R 3  are independently selected from the group consisting of hydrogen, methyl, halogen, trifluoromethyl, and cyano; and  
 R 4  is selected from the group consisting of  
                     
  where R 5  is selected from the group consisting of substituted and unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, O—R 7 , NR 8 R 9 , C 1 -C 8  alkyl, and monocyclic heterocycloalkyl, R 6  is selected from the group consisting of substituted and unsubstituted aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkenyl, O—R 7 , C(O)R 7 , NR 8 R 9 , C 2 -C 8  alkyl, and monocyclic heterocycloalkyl, where R 7  is selected from the group consisting of substituted and unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, R 8  is selected from the group consisting of hydrogen and substituted and unsubstituted alkyl, and R 9  is selected from the group consisting of substituted and unsubstituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;  
 
         or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof.  
       
     
     
         7 . A compound according to  claim 6 , wherein: 
 X is selected from the group consisting of CH 2 , O, and S;    Y is selected from the group consisting of CH 2  and S, provided that at least one of X and Y is CH 2 ;    R 2  and R 3  are independently selected from the group consisting of hydrogen, methyl, fluorine, and chlorine; and    R 4  is selected from the group consisting of                         where R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted aryl and heteroaryl;    or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite.      
     
     
         8 . A compound according to  claim 7 , wherein R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted aryl; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite.  
     
     
         9 . A compound according to  claim 7 , wherein R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted heteroaryl; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite.  
     
     
         10 . A compound according to  claim 7 , wherein: 
 X is CH 2 ;    Y is S;    R 2  and R 3  are independently selected from the group consisting of hydrogen, methyl, fluorine, and chlorine; and    R 4  is selected from the group consisting of                           where R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted aryl and heteroaryl;    or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite.    
     
     
         11 . A compound according to  claim 10 , wherein R 5  and R 6  are each independently selected from the group consisting of substituted and unsubstituted aryl; or a pharmaceutically acceptable salt, a pharmaceutically acceptable prodrug, or a pharmaceutically active metabolite thereof, or a pharmaceutically acceptable salt of said metabolite.  
     
     
         12 . A compound selected from the group consisting of 
 N-(3,4,5-Trimethoxyphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;    N-(3,4,5-Trimethoxyphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide;    N-(4-Isopropyl-3-methylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;    N-(4-Isopropyl-3-methylphenyl)-3-[(5-amino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide;    N-(4-Isopropyl-3-methylphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;    N-(2-Methylquinolin-6-yl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;    N-(3-Isopropylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;    N-(3,5-Dibromo-4-methylphenyl)-3-[(pyrazin-2-yl)sulfanylmethyl]benzamide;    N-(3,4,5-Trimethoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;    N-(3,4,5-Trimethoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;    N-(Quinolin-6-yl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanyl-methyl]benzamide;    N-(5-Methylisoxazol-3-yl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;    N-(Pyridin-4-yl)methyl-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;    N-(1,3-Benzodioxyl-5-ylmethyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]benzamide;    N-(2-Methoxybenzyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]benzamide;    N-(2-Phenylethyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]benzamide;    N-(2-Methoxyphenyl)-3-[(1H-pyrazolo[3,4-d]pyrimidin-4-yl)-sulfanylmethyl]benzamide;    N-[3-(N-Methyl-N-phenylamino)propyl]-3-[(5-methyl-1H-1,2,4-triazol-3-yl) sulfanylmethyl]benzamide;    N-(1,3-Benzodioxyl-5-ylmethyl)-3-[(5-methyl-1H-1,2,4-triazol-3-yl)sulfanylmethyl]benzamide;    N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl-sulfanyl) methyl]benzamide;    N-(3,3-Diphenylpropyl)-3-{[(5-methyl-1H-1,2,4-triazol-3-yl)-sulfanyl]methyl}benzamide;    3-[(5-Methyl-1H-1,2,4-triazol-3-yl)-sulfonyl]methyl}-N-phenethylbenzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-isopropylphenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-trifluoromethyl-5-methoxyphenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3,5-bis-trifluoromethylphenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-t-butylphenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-isopropylphenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-trifluoromethoxyphenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3,5-dimethylphenyl)-benzamide:    3[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-(2-hydroxyethyl)phenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(4-dimethylaminophenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-trifluoromethylsulfonyl phenyl)-benzamide;    3-[(1H-Pyrazolo[3,4-d]pyrimidin-4-yl)sulfanylmethyl]-N(3-dimethylaminophenyl)-benzamide;    3-[(5-Cyanoamino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]-N-(3,4,5-trimethoxyphenyl) benzamide;    3-[(5-(Methoxycarbonylamino)-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]-N-(3,4,5-trimethoxyphenyl)benzamide;    N-(3,4,5-Trimethoxyphenyl)-3-[(5-acetylamino-2H-[1,2,4]triazol-3-yl)sulfanylmethyl]benzamide;    N-(4-Isopropyl-3-methylphenyl)-3-[(pyrazin-2-yl)methylsulfanyl]benzamide;    N-(2-Methylquinolin-6-yl)-3-[(pyrazin-2-yl)methylsulfanyl]benzamide;    N-(2-Methyl-quinolin-6-yl)-3-(pyridin-3-ylmethylsulfanyl)-benzamide dihydrochloride;    N-(2-methyl-quinolin-6-yl)-3-[{5-(phenylamino)-2-H-pyrazol-3-yl}methylsulfanyl]benzamide;    N-(3,4,5-trimethoxyphenyl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]benzamide;    3-[{5-((E)-2-(4-Hydroxy-3-methoxyphenyl)ethenyl)-2H-pyrazol-3-yl}-methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide;    3-[5-(2-(3,4-Dimethoxyphenyl)ethenyl)-2H-pyrazol-3-yl)methylsulfanyl]-N-(2-methylquinolin-6-yl)benzamide;    3-(2-{5-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-2H-pyrazol-3-yl}-ethyl)-N-(3-methyl-4-isopropylphenyl)-benzamide;    4-Fluoro-3-[{5-((E)-1-propenyl)-2H-pyrazol-3-yl}methoxy]-N-[4-(pyrrolidin-1-yl)-3-trifluoromethylphenyl]benzamide;    3-(2-{5-[(E)-2-(3,4-Dimethoxyphenyl)ethenyl]-2H-pyrazol-3-yl}-ethyl)-N-(3-methyl-4-isopropylphenyl)-benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-3-{2-[5-(4-(methylsulfamoyl)-phenylamino)-2H-pyrazol-3-yl]-ethyl}-benzamide;    N-(2-Methylquinolin-6-yl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]benzamide;    N-(4-isopropyl-3-methylphenyl)-3-[2-(5-phenylamino-2H-pyrazol-3-yl)ethyl]benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-benzamide;    N-(4-Dimethylamino-3-trifluoromethylphenyl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}-benzamide;    N-(6-Dimethylamino-5-trifluoromethylpyridin-3-yl)-3-{2-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}-benzamide;    N-(3,5-Dichloro-4-dimethylaminophenyl)-3-{2-[5-(6-methoxy-pyridin-3-yl)amino-2H-pyrazol-3-yl]ethyl}benzamide;    3-{2-[5-(6-Methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-N-(4-pyrrolidin-1-yl-3-trifluoromethylphenyl)benzamide;    3-{2-[5-(6-Methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]-ethyl}-N-[4-(4-t-butoxycarbonylpiperazin-1-yl)-3-trifluoromethylphenyl]benzamide;    3-{2-[5-(6-Methoxypyridin-3-yl)amino)-2H-pyrazol-3-yl]ethyl}-N-(4-piperazin-1-yl-3-trifluoromethylphenyl)benzamide;    4-Fluoro-3-[{5-(pyridin-3-yl)amino-2H-pyrazol-3-yl}methoxy]-N-[((4-pyrrolidin-1-yl)-3-trifluoromethylphenyl)benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-3-[2-(5-phenylamino-2-H-pyrazol-3-yl)-cyclopropyl]-benzamide;    3-[({3-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-5-yl}methyl)amino]-N-(3-methyl-4-isopropylphenyl)benzamide;    3-[({5-[(E)-2-(4-hydroxy-3-methoxyphenyl)ethenyl]-1H-pyrazol-3-yl}methyl)amino]-N-phenyl)benzamide;    4-Fluoro-N-[4-(imidazol-1-yl)-3-trifluoromethylphenyl]-3-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-ylmethoxy]-benzamide;    4-Fluoro-3-[5-(6-methoxy-pyridin-3-yl)amino-2H-pyrazol-3-yl]methoxy-N-(4-pyrrolidin-1-yl-3-trifluoromethyl-phenyl)-benzamide;    4-Fluoro-3-[5-(6-methoxypyridin-3-yl)amino-2H-pyrazol-3-yl]methoxy-N-(3-methoxy-5-trifluoromethyl-phenyl)-benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-3-(Isoquinolin-4-yl)methoxy-benzamide;    3-(Isoquinolin-4-yl)methoxy-N-(3,4,5-trimethoxyphenyl)benzamide hydrochloride;    3-(Isoquinolin-4-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide hydrochloride;    3-(Isoquinolin-4-yl)methoxy-N-(2-methyl-4-methylsulfanyl-quinolin-6-yl)-benzamide hydrochloride;    3-(Pyridin-3-yl)methoxy-N-(3,4,5-trimethoxyphenyl)benzamide;    N-(Naphthalen-2-yl)-3-(pyridin-3-yl)methoxybenzamide;    N-(1-Allyl-1H-indol-5-yl)-3-(pyridin-3-yl)methoxy-benzamide;    3-(Pyridin-3-yl)methoxy-N-quinolin-6-yl-benzamide;    N-(2-Methyl-quinolin-6-yl)-3-(pyridin-3-yl)methoxy-benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-4-fluoro-3-(Isoquinolin-4-yl)methoxy-benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-4-methyl-3-(Isoquinolin-4-yl)methoxy-benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-4-chloro-3-(Isoquinolin-4-yl)methoxy-benzamide;    3-(6-Aminopyridin-3-yl)methoxy-N-(4-Isopropyl-3-methyl-phenyl)benzamide;    3-(6-Aminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide;    3-(6-Acetylaminopyridin-3-yl)methoxy-N-(2-methyl-quinolin-6-yl)-benzamide;    3-(6-Acetylaminopyridin-3-yl)methoxy-N-(4-isopropyl-3-methyl-phenyl)-benzamide;    4-Fluoro-N-(1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamide bistrifluoroacetic acid salt;    N-(2,2-difluorobenzo[1,3]dioxol-4-yl-ethyl)-benzamide trifluoroacetic acid salt;    4-Fluoro-N-(2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-3-(isoquinolin-4-yl-methoxy)-benzamide bistrifluoroacetic acid salt;    N′-{4-[3-(4-Isopropyl-3-methyl-phenylcarbamoyl)-phenoxy;    N-(4-Isopropyl-3-methyl-phenyl)-3-{1-[N′-(3-methoxy-benzylidene)-hydrazino]-isoquinolin-4-ylmethoxy}-benzamide;    N-(3,5-Diallyl-4-methyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide;    N-(3,5-Dibromo-4-methyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide;    3-(Isoquinolin-4-ylmethoxy)-N-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-benzamide;    3-(Isoquinolin-4-ylmethoxy)-N-(3-trifluoromethoxy-phenyl)-benzamide;    N-(2,4-Dimethylquinolin-6-yl)-3-(isoquinolin-4-ylmethoxy)-benzamide;    3-(Isoquinolin-4-ylmethoxy)-benzoic acid N′-(4-trifluoromethyl-phenyl)-hydrazide;    N-Benzyloxy-3-(isoquinolin-4-ylmethoxy)-benzamide;    3-(Isoquinolin-4-ylmethoxy)-benzoic acid N′-phenyl-hydrazide;    N-(5,7-dimethyl 1,8]naphthydrin-2-yl)-3-(isoquinolin-4-ylmethoxy)-benzamide;    3-(Isoquinolin-4-ylmethoxy)-N-(1,1,3,3-tetramethyl-1,3-dihydroisobenzofuran-5-yl)-benzamide;    N-(3,5-Dichloro-4-pyrrolidin-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;    4-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(pyridin-3-ylmethoxy)-benzamide;    4-Fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl-3-3-(pyridin-3-yl)methoxybenzamide;    4-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide;    4-Fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-3-(isoquinolin-4-ylmethoxy)-benzamide; 4-Fluoro-N-(4-morpholin-4-yl-3-trifluoromethyl-phenyl)-3-(quinolin-3-ylmethoxy)-benzamide;    4-Fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-3-(quinolin-3-ylmethoxy)-benzamide;    N-(3,5-Dichloro-4-morpholin-4-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;    N-(3,5-Dichloro-4-piperazin-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;    4-Fluoro-N-[4-(piperazin-1-yl)-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide;    4-Fluoro-N-(4-(imidazol-1-yl-3-trifluoromethylphenyl]-3-(pyridin-3-yl)methoxybenzamide;    4-Fluoro-N-(4-pyrazol-1-yl-3-trifluoromethyl-phenyl)-3-(pyridin-3-ylmethoxy)-benzamide;    4-Fluoro-3-(pyridin-3-ylmethoxy)-N-(4-[1,2,4]triazol-1-yl-3-trifluoromethyl-phenyl)-benzamide;    N-(3,5-Dichloro-4-imidazol-1-yl-phenyl)-4-fluoro-3-(pyridin-3-ylmethoxy)-benzamide;    3-(5-Bromo-pyridin-3-ylmethoxy)-4-fluoro-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide;    3-(2-Isoquinolin-4-yl-ethyl)-N-phenyl-benzamide;    3-(2-Isoquinolin-4-yl-ethyl)-N-(3,3,5-trimethyl-cyclohexyl)-benzamide;    N-(4-Isopropyl-3-methyl-phenyl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide;    3-(2-Isoquinolin-4-yl-ethyl)-N-(2-methyl-quinolin-6-yl)-benzamide;    N-(3,5-Dibromo-4-methyl-phenyl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide;    N-(4,6-Dimethyl-pyridin-2-yl)-3-(2-isoquinolin-4-yl-ethyl)-benzamide;    2-Chloro-4-fluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide;    2,4-Difluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide;    2-Fluoro-N-(4-isopropyl-3-methyl-phenyl)-5-(2-isoquinolin-4-yl-ethyl)-benzamide;    N-(2-Methyl-quinolin-6-yl)-3-(2-pyridin-3-yl-ethyl)-benzamide hydrochloride;    N-(4-Isopropyl-3-methyl-phenyl)-3-(2-pyridin-3-yl-ethyl)-benzamide;    N-(3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-ylsulfanylmethyl]phenyl}-(3-bromo-4-methyl) benzamide;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-ylsulfanylmethyl]phenyl}-3,5-bis(trifluoromethyl) benzamide;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-hydroxy-3-methoxy) benzamide;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-hydroxy-3-t-butyl) benzamide;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-4-t-butylbenzamide;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(4-phenoxy)benzamide;    N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl]phenyl}-N′-[3,5-bis-(trifluoromethyl)phenyl]urea;    N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl]phenyl}-N′-(pyridin-3-yl)urea;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-(3,5-di-t-butyl) benzamide;    3-Bromo-4-hydroxy-N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-benzamide;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-quinoline-6-carboxamide;    5-Fluoro-N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-indole-2-carboxamide;    N-{3-[(1H-pyrazolo[3,4-d]-pyrimidin-4-yl)sulfanylmethyl]phenyl}-indole-6-carboxamide;    (R/S)-2-(2-methylphenyl)-N-{3-[(1H-pyrazolo[3,4-d]pyrimidin-4-ylsulfanyl)methyl)-methyl]phenyl}butanamide;    3-t-Butyl-4-hydroxy-N-{3-[5-(6-methoxy-pyridin-3-ylamino)-2H-pyrazol-3-ylmethyl sulfanyl]-phenyl}-benzamide;    3-t-Butyl-4-hydroxy-N-[3-(pyridin-3-ylmethylsulfanyl)-phenyl}-benzamide;    3-t-Butyl-4-hydroxy-N-[3-(isoquinolin-4-ylmethylsulfanyl)-phenyl}-benzamide;    [3-(5-Bromo-pyridin-3-ylmethoxy)-phenyl]-3-t-butyl-4-hydroxy-benzamide;    4-Acetoxy-3-t-butyl-N-[3-(pyridin-3-ylmethoxy)phenyl]-benzamide;    4-Acetoxy-3-t-butyl-N-[3-(isoquinolin-4-ylmethoxy)phenyl]-benzamide;    3-t-Butyl-4-hydroxy-N-[3-(pyridin-3-ylmethoxy)-phenyl]-benzamide;    3-t-Butyl-4-hydroxy-N-[3-(isoquinolin-4-ylmethoxy)-phenyl]-benzamide;    1-[3-(pyridin-3-ylmethoxy)phenylcarbamoyl]pyrrolidine;    4-[3-(pyridin-3-ylmethoxy)phenylcarbamoyl]morpholine;    3-[{6-Methoxy-7-(2-methoxyethoxy)cinnolin-4-yl}sulfanylmethyl]-N-phenyl-benzamide;    3-[2-(6-Acetylamino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoro-methylphenyl)-benzamide dihydrochloride;    3-[2-(6-Amino-pyridin-3-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide dihydrochloride;    3-[2-(3H-Imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide dihydrochloride;    5-{2-[3-(Piperazin-1-yl-trifluoromethyl-phenylcarbamoyl)-phenyl]-ethyl}-nicotinamide dihydrochloride;    5-{2-[3-(Piperazin-1-yl-trifluoromethyl-phenylcarbamoyl)-phenyl]-ethyl}-nicotinic acid methyl ester dihydrochloride;    4-Fluoro-3-[2-(3H-imidazo[4,5-b]pyridin-6-yl)-ethyl]-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide dihydrochloride; and    4-Fluoro-3-(5-furan-2-yl-pyridin-3-ylmethoxy)-N-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-benzamide dihydrochloride;    or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof or a pharmaceutically acceptable salt of said metabolite.    
     
     
         13 . A compound selected from the group consisting of the compounds corresponding to Example B-27 (Compounds 1-244), Example V-6d (Compounds 1-176), Example V-7b (Compounds 1-43) and Example V-14 (Compounds 1-88), or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite thereof or a pharmaceutically acceptable salt of said metabolite.  
     
     
         14 . A pharmaceutically acceptable salt of a pharmaceutically active metabolite of a compound according to  claim 1 .  
     
     
         15 . A pharmaceutical composition for modulating or inhibiting the activity of a protein kinase receptor comprising: 
 (a) a therapeutically effective amount of an agent selected from the group consisting of a compound according to  claim 1 , a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite thereof, and a pharmaceutically acceptable salt thereof; and    (b) a pharmaceutically acceptable carrier, diluent, or vehicle therefor.    
     
     
         16 . A pharmaceutical composition for modulating or inhibiting the activity of a protein kinase receptor comprising: 
 (a) a therapeutically effective amount of a pharmaceutically acceptable salt of a pharmaceutically active metabolite of a compound according to  claim 1;     (b) a pharmaceutically acceptable carrier, diluent, or vehicle therefor.    
     
     
         17 . A method of treating a mammalian disease condition mediated by protein kinase activity, comprising administering to a mammal in need thereof a therapeutically effective amount of an agent selected from the group consisting of a compound according to  claim 1 , a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite thereof, and a pharmaceutically acceptable salt thereof.  
     
     
         18 . A method according to  claim 17 , wherein the mammalian disease condition is associated with tumor growth, cell proliferation, or angiogenesis.  
     
     
         19 . A method of modulating or inhibiting the activity of a protein kinase receptor, comprising contacting the kinase receptor with an effective amount of an agent selected from the group consisting of a compound according to  claim 1 , a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite thereof, and a pharmaceutically acceptable salt thereof.  
     
     
         20 . A method according to  claim 19 , wherein the protein kinase receptor is a VEGF receptor.